The present invention is directed to providing new compounds for preventing and/or treating a skin disorder, more particularly an aesthetic disorder of the skin. The present invention concerns more particularly the defects or disorders of the skin and/or its appendages that are linked to an imbalance in the differentiation and/or proliferation of the cells of the epidermis.
By “skin”, is meant the entirety of the skin on the body, including the scalp and the mucosae. By “appendages of the skin” are meant the body hairs, eyelashes, head hair and nails.
The epidermis, the surface part of the skin, is a tissue in which the cells are joined together and interlinked with one another, and lie on a basal membrane. The epidermis forms an outer coating which comprises sebaceous or sweat glands and hair follicles. It is divided conventionally into a basal layer of keratinocytes comprising, in particular, skin stem cells, and constituting the germinal layer of the epidermis; a spinous layer consisting of a number of layers of polyhedral cells disposed on the basal layer; a “granular” layer comprising one to three layers of “flattened cells” containing distinct cytoplasmic inclusions, keratohyalin granules; and, lastly, an assembly of upper layers, referred to as the horny layer or stratum corneum (SC), consisting of keratinocytes at the terminal stage of their differentiation, referred to as corneocytes.
The stratum corneum, the outermost part of the skin, which provides the barrier function between the organism and the environment, and the hair stem, which is the emergent part of the hair follicle that constitutes the head of hair, both represent the outcome of the keratinocyte differentiation process. Epidermal differentiation follows a process of maturation in which keratinocytes in the basal layer differentiate and migrate so as to result in the formation of the corneocytes, which are dead cells that are completely keratinized. This differentiation is the result of very well coordinated phenomena which will lead to maintenance of epidermal homeostasis and will give the skin a healthy, youthful, luminous and smooth appearance.
During ageing, many physiological deteriorations in the skin occur, resulting from dysfunction of epidermal homeostasis, and in particular from dysfunction of epithelial differentiation of keratinocytes and/or of proteoglycan synthesis. The deteriorations in epidermal homeostasis are manifested primarily in a decrease in the differentiation of the keratinocytes, giving rise to a deficit in the protein matrix of the horny cells, in an increase in metalloproteases, and in their extracellular matrix-degrading activity, and also in a decrease in the synthesis of the various glycosaminoglycans. These deteriorations are also manifested, generally, in the appearance of a more marked microrelief of the skin, and even of fine lines, and eventually in the presence of deep wrinkles, a loss of elasticity, a coarse feel, and skin dryness. Histologically, a flattening of the dermal-epidermal junction and a decrease in the thickness of the dermis and epidermis are observed. The skin's collagen content and glycosaminoglycan content are also decreased, and the barrier function of the aged skin may be impaired.
Furthermore, the stratum corneum, by virtue of its solid nature and its compact, stratified structure, provides a barrier function: in particular it opposes transcutaneous water loss, also referred to as “insensible water loss”. Accordingly, one of the functions of the stratum corneum is to take up and retain the water present in the epidermis, and any deterioration in SC structure and/or SC function may be manifested in changes to cutaneous moisturization. Moisturization is provided to the skin by the water in the deep-lying layers and by perspiration. A skin moisturization imbalance may be manifested in profound consequences, both physiological and cosmetic.
Cutaneous moisturization disorders, and especially skin dryness, are often observed with age and/or changes in climate. However, such conditions may also be manifested in young individuals.
The condition of skin dryness may have an acquired or non-pathological, constitutional origin, or may have a pathological constitutional origin.
Numerous external factors may lead to the skin drying out or may aggravate this condition. These factors include climate conditions such as cold or wind, solar radiation, and exposure to certain chemical or therapeutic agents.
Physiologically, dry skin is often associated with a drop in the level of skin moisturization and with an alteration in the process of maturation of the stratum corneum, the most visible sign of this being the appearance of squamae at the skin surface. In sensory terms, dry skin may be characterized by a sensation of tautness and/or of skin tension.
Many epidermal factors whose expression, biological activity or maturation are impaired, reduced or increased are known to be involved, directly or indirectly, in the incidence and manifestation of defects or disorders of the skin and/or its appendages that are linked to an imbalance in the differentiation and/or proliferation of cells of the epidermis, and more particularly of aged skin or cutaneous signs of ageing, or of dry skin or signs of skin dryness.
Furthermore, in the patent applications filed under numbers FR 10 601 83 and FR 10 601 79, a description was given of how the interaction between SASPase and FLG2 gives rise to an increase in the proteolytic activity of SASPase. This proteolytic activity is implicated in the breakdown of corneodesmosin, and, consequently, plays a part in the regulation of epidermal homeostasis, in particular through regulating phenomena of desquamation, of proliferation or of differentiation of the cells. Moreover, this function of SASPase was confirmed by the observation of its capacity to hydrolyse certain forms of filaggrin, a protein essential to the organization, function and moisturizing of the epidermal barrier (Matsui et al., EMBO Mol Med, 2011, 3:320).
The possession of active compounds, in particular pyrido-pyrimidine derivatives, capable of modulating this interaction therefore proves to be a major component in producing a cosmetic or therapeutic arsenal to counter defects or disorders of the skin and/or its appendages that are linked to an imbalance in the differentiation and/or proliferation of the cells of the epidermis.
A number of pyrido-pyrimidine derivatives are known, for example, from JP 59-225, 188, Sarma et al. (2010; Molecular Diversity; vol. 15, no. 3, pp. 697-705), Pastor (1994; Tetrahedron; vol. 50, no. 27, pp. 8085-8098), Verma et al. (2012; Tetrahedron; pp. 2595-2600); Agarwal et al. (2005; Tetrahedron Letters; vol. 46, no. 8, pp. 1345-1348), or Kajino & Meguro (1990; Heterocycles. International Journal for Reviews and Communications in Heterocyclic Chemistry; vol. 31, no. 12, pp. 2153-2161).
None of those documents teaches pyrido-pyrimidine derivatives in accordance with the invention and/or the implementation of pyrido-pyrimidine derivatives for preventing and/or treating an aesthetic defect in the skin and/or its appendages that is associated with an imbalance in the differentiation and/or proliferation of the cells of an epidermis.
It is therefore very important to find new targets, new active compounds which act on the origin of the defects or disorders in the skin and/or its appendages that are linked to an imbalance in the differentiation and/or proliferation of the cells of the epidermis.
Accordingly, there remains a need for new actives that are capable of exerting a beneficial cosmetic or therapeutic action on aged skin.
There is also a need for new actives that are capable of exerting a preventive and/or care action with regard to aged skin, this action being durable over time.
There further exists a need for new actives or new treatments for promoting and/or reinforcing the moisturizing of the skin.
There is also a need for new actives or new treatments for preventing and/or treating dry skin or signs of skin ageing.